Anemia Of Chronic Kidney Disease Research Articles

Iron Deficiency Anemia in Patients with Chronic Renal Insufficiency at Tertiary Care Hospital in Northern Punjab

Anemia is a frequently encountered complication of chronic kidney disease (CKD) leading to worse outcomes in terms of quality of life and premature death. However, the current prevalence of iron deficiency anemia (IDA) in CKD is understudied in Pakistan. Objective: To assess the frequency of IDA in patients with CKD at Bewal International Hospital, Gujar Khan, Pakistan. Methods: A cross-sectional was executed at the Department of Nephrology, Bewal International Hospital, Pakistan from January 1, 2022, to June 30, 2022. The study comprised 97 patients aged >13 years of either gender having CKD (GFR <60 ml/min/1.73m²) for at least 90 days. All patients were tested for serum creatinine, ferritin, and hemoglobin levels. IDA was considered if hemoglobin was ≤12 mg/dL in women and ≤13 mg/dL in men. Results: Among 97 patients, there were 57(58.7%) males and 40(41.3%) females. The mean age was 51.23 ± 12.99 years while the mean disease duration was 6.01 ± 1.610 years. 57(58.7%) patients had IDA. IDA was more frequent in women with CKD (67.5%), compared to men (52.64%). However, this association was statically insignificant (p>0.05). When data was stratified, a substantial association was found between IDA and the stage of CKD (p=0.007). There was no significant association between IDA and disease duration (p>0.05). Conclusions: It was concluded that anemia is common in CKD patients, with a high prevalence in females. Stage 3–5 CKD is significantly associated with developing iron deficiency anemia. Early identification and timely management can avoid unfavorable outcomes in these patients.

Anemia of Chronic Kidney Disease-A Narrative Review of Its Pathophysiology, Diagnosis, and Management.

Anemia is one of the most common chronic kidney disease (CKD) complications. It negatively affects patients' quality of life and clinical outcomes. The pathophysiology of anemia in CKD involves the interplay of various factors such as erythropoietin (EPO) deficiency, iron dysregulation, chronic inflammation, bone marrow dysfunction, and nutritional deficiencies. Despite recent advances in understanding this condition, anemia still remains a serious clinical challenge in population of patients with CKD. Several guidelines have been published with the aim to systematize the diagnostic approach and treatment of anemia; however, due to emerging data, many recommendations vary between publications. Recent studies indicate a potential of novel biomarkers to evaluate anemia and related conditions such as iron deficiency, which is often present in CKD patients. Our article aims to summarize the pathophysiology of anemia in CKD, as well as the diagnosis and management of this condition, including novel therapeutic approaches such as hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI). Understanding these complex subjects is crucial for a targeted approach to diagnose and treat patients with anemia in CKD effectively.

#2815 Single center, single arm, prospective, observational study of desidustat in chronic kidney disease-induced anemia

Abstract Background and Aims Anemia in chronic kidney disease (CKD) is multifactorial. Relative deficiency of erythropoietin is one of the key reasons for decreased RBC production. This anemia is associated with poor quality of life and increases morbidity in CKD patients. Injectable erythropoietin is the standard of care for CKD-anemia, which has safety concerns. Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), stimulates endogenous erythropoiesis and is approved for CKD anemia treatment. Hence, the present study identifies the real-world clinical efficacy and safety of the desidustat treatment for a short duration in CKD anemia. Method This is an open-label, single-center, prospective study. We analyzed the data of 130 patients who are currently in follow-up and received Desidustat as treatment for CKD-anemia. The study is for the duration of 24 weeks. We followed up on patent at 1 month, 3 months, and the end of the study (6 months). Patients were given a 100-mg Desidustat tablet orally three times in a week. The primary outcome is to assess the change in Hb from baseline, and the secondary outcome is the safety of the therapy. Results In this study, we enrolled 130 patients. Of these 130 patients, 58.4% (n = 76) were male and 41.5% (n = 54) were female. The mean age of the study population was 53.6 ± 12.3 years. The majority of the study population was in the pre-dialysis category; 80% (n = 104) and 20% (n = 26) were on dialysis. All the dialysis patients were on three times per week on Dialysis. Diabetes (68%) and hypertension (75%) are the most common co-morbid conditions in patients with CKD anemia. All the patients received desidustat at a 100 mg, three-weekly dose. During each follow-up visit, a significant rise in hemoglobin was observed (p<0.001), as shown in the figure. With desidustat therapy, adverse drug reactions were seen in 5.3% (n = 7) cases: three cases of abdominal pain, two cases of vomiting, and two cases of diarrhea. Conclusion Oral HIF-PHIs and Desidustat showed significant improvement in hemoglobin in CKD anemia patients. More studies require for safety and efficacy in Dialysis dependent CKD - Anemia patients.

#708 Retrospective analysis of the real-world experience of desidustat in the treatment of chronic kidney disease induced anemia

Abstract Background and Aims Chronic kidney disease (CKD) is commonly associated with an increased risk of anemia, which significantly impacts patients' quality of life and increases morbidity and mortality. Current treatment options for anemia in CKD, such as injectable erythropoiesis-stimulating agents (ESAs) have limitations and safety concerns. Desidustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) has shown promise in stimulating endogenous erythropoiesis and addressing anemia in CKD. Therefore, the present study assesses the real-world clinical efficacy and safety of the desidustat treatment for a short duration of 6 months (24 weeks) in CKD patients with anemia. Method This is a retrospective analysis of 140 patients at our center who received Desidustat as a treatment for CKD anemia. Desidustat was initiated in all patients at 100 mg three times a week. Dose adjustment was done every 4 weeks as per the Hb level of the patient. The duration of the study was 6 months. The primary endpoint of the present study was a change in Hb from baseline with desidustat therapy and the secondary endpoint was safety of the treatment. Results The majority of the patients were Pre-dialysis 74.28% (n = 104) and 25.72% (n = 36) were dialysis-dependent patients. Of 36 dialysis-dependent patients; 75% (n = 27) were on dialysis three times a week, rest were on twice-a-week dialysis. In the current study, the majority of patients had Hypertension (95.7%) and diabetes (68.57%) as co-morbidities. All the patients in the current study were maintained with 100 mg Desidustat, however, 9.2% (n = 13) required dose reduction, and 11.42% (n = 16) required an increased dose of desidustat on the follow-up visit. In both Pre-Dialysis and dialysis-dependent patients, there was a sustainable rise in the mean Hb levels at the end of 24 weeks from baseline (1.05 g/dL; p < 0.05) All the patients tolerated desidustat well. In the present study, we didn't observe significant side effects related to the therapy apart from 2.41% (n = 3) cases of Diarrhoea and Vomiting. Conclusion Desidustat is effective in increasing Hb in CKD Anemia patients in the short run. However, Long-term studies are required to establish the efficacy and safety of this novel therapy.

#1171 Effect of methoxy polyethylene glycol-epoetin beta on delaying dialysis in anemic patients with Stage 4-5 chronic kidney disease

Abstract Background and Aims The optimal hemoglobin (Hb) target for treating anemia in pre-dialysis chronic kidney disease (CKD) remains controversial. This study investigates the efficacy and safety of methoxy polyethylene glycol-epoetin beta, in delaying the initiation of kidney replacement therapy (KRT), all-cause mortality, CKD progression, and quality of life in stage 4-5 CKD patients. It compares outcomes between patients targeting an Hb level of 10.5-11.5 g/dL versus 8.5-9.5 g/dL. Method This was a single-center, open-label, parallel-group randomized controlled trial. Patients with estimated glomerular filtration rates (eGFR) of 8-15 ml/min/1.73 m2, who had not yet started dialysis, were randomized into two groups based on different Hb targets (Group A: 10.5-11.5 g/dL, Group B: 8.5-9.5 g/dL). Methoxy polyethylene glycol-epoetin beta (MIRCERA®) was prescribed by a pre-specified protocol to achieve these Hb targets. Iron supplements were administered to maintain transferrin saturation >20% or serum ferritin >200 ng/ml. Primary outcomes included a composite of all-cause death and KRT initiation, with secondary outcomes encompassing eGFR slope, hospitalization incidence, blood transfusion necessity, and quality of life measured by the 36-Item Short Form Health Survey (SF-36). Results A total of 62 participants were randomized. The mean age was 64.0 years (SD ±16.0), with 51.6% being female. The mean estimated Glomerular Filtration Rate (eGFR) at enrollment was 12.1 ml/min/1.73 m2 (SD ±3.1). Group A had a significantly higher time-averaged Hemoglobin (Hb) level (10.5 g/dL, SD ±1.2) compared to 8.5 g/dL (SD ±0.9) in the control group (p < 0.001). There was no significant difference in the composite endpoint of all-cause death and Kidney Replacement Therapy (KRT) initiation between the two groups (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.32-1.50; p = 0.35, as shown in the Figure). The eGFR slope was similar in both groups (−2.54 vs. −2.53 ml/min/1.73 m2 per year, p = 0.9). Time-averaged ferritin, transferrin saturation, blood pressure, and dietary sodium/protein intake showed no significant differences. Participants in the lower Hb target group required more blood transfusions (11 vs 1 unit, Incidence Rate Ratio [IRR] = 0.075, 95% CI 0.002-0.517, p = 0.001). Rates of hospital admissions, and changes in SF-36 quality of life domains were comparable between the groups, as detailed in the Table. Conclusion The study indicates that using methoxy polyethylene glycol-epoetin beta to maintain a higher Hb target in anemic patients with stage 4-5 CKD does not significantly alter the rate of all-cause mortality, the initiation of KRT, and rate of eGFR decline compared to a lower Hb target. However, a higher Hb target may reduce the need for blood transfusions without adversely affecting the progression of CKD, hospitalization rates, or quality of life. These findings suggest that while higher Hb targets may not dramatically alter key clinical outcomes, they could offer benefits in reducing transfusion requirements, thus providing a more nuanced approach to managing anemia in late-stage CKD.

#1122 Anaemia in CKD and cardiovascular risk; all cut from the same cloth?

Abstract Background and Aims Anaemia in chronic kidney disease (CKD) has been repeatedly associated with increased cardiovascular morbidity and mortality, but most studies have not investigated its longitudinal association by sex and age. Our aim was to study the association between haemoglobin (Hb) current value and the hazard of major adverse cardiovascular event (MACE) in specific subgroups of CKD patients defined by age and sex. Because erythropoiesis-stimulating agents (ESA) are incriminated to modify the effect of Hb level on the hazard of event for high level of Hb, we have here only focused in non-ESA users CKD patients. Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. We included patients with at least one Hb, estimated glomerular filtration rate (eGFR), transferrin saturation (TSAT) or ferritin measurement. We studied all Hb measurements available until a first MACE defined as the first event among cardio-vascular death, myocardial infarction, stroke or hospitalization for acute heart failure; initiation of kidney replacement therapy; death from other causes; or initiation of ESA therapy, whichever came first. First, we estimated the individual trajectories of Hb, eGFR, TSAT, ferritin using multivariate share random effect joint model. Then, we estimated the association between Hb current value and MACE using a cause specific multivariate Cox model in 4 specific subgroups separately: women ≤ and >70 years, men ≤ and >70 years. All models were adjusted on current value of eGFR, TSAT, Ferritin, and baseline value of albumin-to-creatinine ratio, age, CKD aetiology, heart failure past history, alcohol consumption, iron treatment, antithrombotic and anticoagulant. When appropriate, spline functions were used for continuous variables to account for potential non-linear effects. Reference value of Hb for computing hazard ratio was 12 g/dL in women, and 13 in men according to current definition of anaemia. Results A total of 2742 patients were included in the analysis (median eGFR 33 ml/min/1.73 m2, median age at inclusion 69 years) together with 28423 Hb measurements (median of 13 per patient) collected during a median follow-up of 5.0 years. There were 551 women ≤70 (median Hb 12.4 g/dL, 34 (6.2%) MACE), 349 women > 70 (12.2 g/dL, 61 (17.5%) MACE), 1009 men ≤ 70 (13.4 g/dL, 104 (10.3%) MACE) and 833 men > 70 (13.0 g/dL, 163 (19.6%) MACE). No statistical significant association was found in males whatever their age (Hazard ratio of MACE for each 1 g/dL increase in Hb 1.0 (95% CI 0.9-1.1) in men < 70 and 0.9 (95% CI 0.8-1.1) in men > 70). For women, the hazard of MACE raised as the Hb values decreased, with a more pronounced increase in women > 70 (Fig. 1). For example, the hazard ratio for a Hb value of 10 g/dL compared to the reference was 2.0 (95% CI 0.9-4.7) in women < 70 and 3.3 (95% CI 1.5-7.2) in women > 70. Conclusion In non-ESA users CKD patients, anaemia is associated with the occurrence of MACE in females, especially those older than 70 years. These results raise question about a one-size-fits-all approach in the interpretation of low values of haemoglobin and anaemia management. It also suggests to evaluate the effect of anaemia therapies in men and women separately.

#1194 Roxadustat in ESA converted patients with anemia of chronic kidney disease on dialysis: a secondary analysis of ROXSTAR Registry

Abstract Background and Aims Anemia is associated with increased morbidity & mortality in chronic kidney disease (CKD) patients. Around 20% of patients experience erythropoiesis-stimulating agent (ESA) hypo-responsiveness and can't achieve hemoglobin (Hb) treatment target even with a high dose. Higher ESA dose is associated with undesirable outcomes. Roxadustat has demonstrated efficacy and safety in ESA converted CKD anemia patients. We conduct this secondary analysis of ROXSTAR registry (ChiCTR2100046322) to evaluate the Hb response to roxadustat in ESAs converted dialysis-dependent (DD) patients with prior weekly ESA dose ≥10000 U and <10000 U respectively. Method This study used existing data collected in the ROXSTAR Registry. DD patients converted from ESA treatment who received at least one dose of roxadustat, and had at least one post baseline Hb were included. We described the Hb response to roxadustat treatment in patients converted from higher ESA dose (≥10,000 U per week) and from lower ESA dose (<10,000 U per week) at enrollment. The changes from baseline to week 12 & week 24 in Quality of Life (QoL) assessed by SF-36 Vitality & Physical Function subscales, and Rapid Assessment of Physical Activity (RAPA) Strength & Flexibility scores were also analyzed respectively. Results Total 666 ESA converted DD patients were included. For the higher ESA dose group, there were 426 patients (257 male [60.3%]) with a mean (standard deviation [SD]) age of 49.5 [13.1] years, the median (mix, max) dialysis duration was 31.7 (0.2, 307.8) months. For the lower ESA dose group, 240 patients (141 male [58.8%]) with a mean age of 49.7 [13.0] years were enrolled, and median dialysis duration was 36.4 (0.4, 266.1) months. The mean baseline Hb was 98.0 (14.5) g/L in the higher ESA dose group and 102.2 (12.6) g/L in the lower ESA dose group. The median prior weekly ESA dose was 10000 (10000, 50000) U and 6000.0 (300, 9000) U in higher & lower ESA dose groups (Table 1). Mean weekly roxadustat dose during the first 12 weeks (correction phase) was maintained around 300 mg and then decreased to around 260 mg during 12-52 weeks (maintenance phase) for the higher ESA dose group; the dose started from around 300 mg and decreased to 270 mg during the correction phase and then gradually decreased to around 230 mg during the maintenance phase in the lower ESA dose group. The mean Hb change from baseline averaged over weeks 24-36 & 36-52 was 12.1 [95% CI: 10.5, 13.7] g/L & 12.3 [95% CI: 10.7, 13.9] g/L for the higher ESA dose group and 9.9 [95% CI: 8.0, 11.8] g/L & 10.2 [95% CI: 8.3, 12.1] g/L for the lower ESA dose group, respectively. The proportion (%) of patients with mean Hb ≥100 g/L at the same period were 82.3% [95% CI: 78.1%, 86.6%] & 83.6% [95% CI: 79.3%, 87.9%] in the higher ESA dose group and 88.4% [95% CI: 83.6%, 93.1%] & 89.0% [95% CI: 84.3%, 93.7%] in the lower ESA dose group. There was no clinical meaningful change of QoL observed in either group. Conclusion ESA-converted DD patients responded well to roxadustat in terms of anemia correction and Hb maintenance to treatment target, regardless of prior ESA dose. Similar starting doses of roxadustat were used for both groups and then gradually decreased during the maintenance phase (week 12-52) compared to the correction phase (week 1-12) while the magnitude of dose decrease was greater in the lower ESA dose group.

#511 Inadequate diagnostic investigations and low treatment rates in CKD anemia: an inertia that can only change with long-term follow-up

Abstract Background and Aims Anemia is observed from the early stages in the course of chronic kidney disease (CKD), and as the stage progresses, the severity of anemia and its impact on quality of life increase. Early diagnosis of anemia in chronic kidney disease, assessments related to its etiology, and treatment are therefore crucial. There is no comprehensive and long-term study in Turkey addressing the diagnostic and therapeutic management of anemia seen in the course of chronic kidney disease. The aim of this study is to investigate the frequency of anemia in different stages of CKD in patients diagnosed with Stage 3 and more advanced stages, to evaluate the effectiveness of diagnostic approaches, and management of iron parameters and anemia, and to investigate the effect of anemia on patient survival. We aim to present “real-life” data from this study to guide clinical practice and correct errors or deficiencies in anemia management. Method This study is a single-center, observational-descriptive retrospective study. 1321 outpatients with Stage 3A and advanced CKD and anemia who admitted to Hacettepe University Faculty of Medicine Nephrology Clinic between 2014 and 2018 were included in the study. Data for demographics, CKD etiologies and stages, anemia severities, comorbid diseases were collected from electronic health system (Table 1). Diagnostic investigations for anemia evaluation and therapeutic interventions such as administration of iron, folic acid, vitamin B12, erythropoiesis stimulating agents (ESA) were assessed. The long-term yield of diagnostic and therapeutic approaches and their effects on survival were also evaluated. The study investigated whether the severity of anemia and improvement in anemia had an effect on survival. Results Ferritin is the most commonly performed test for the etiology of anemia (76.4%). Request rates for tests such as B12, folic acid, transferrin saturation and reticulocyte are below 20%. More than half of the patients with anemia (59.4%) have not received any form of anemia treatment. Even among those whose ferritin test was checked and the value was <100 µg/dL, only 41.4% were given iron treatment. As the clinical follow-up period of the patients increased, it was observed that anemia treatment was applied better and target values were reached more frequently (p < 0.001). More than one third of the patients (34.8%) died during follow-up. The overall survival in patients whose anemia improved was 79.8%, and it was 62.8% in patients whose anemia did not improve the overall survival was (p = 0.002) (Fig. 1). When examining the relationship between survival status and anemia severity for the non-dialysis-dependent CKD Stage 3-5 group, there was a statistically significant survival difference between the Hb group of 10-11.9 g/dL to Hb group of <10 g/dL (p = 0.004). Conclusion This study has shown that diagnostic tests for etiology of anemia were insufficiently ordered. It was also found that a significant majority of anemic patients who underwent etiological evaluation were not even adequately treated. Long-term follow up improved anemia treatment, and patients with improved anemia had better survival. In conclusion, we recommend an optimal evaluation of CKD patients with anemia and initiating treatment as early as possible.

#2505 PTEN ablation in osteocytes exacerbates anemia in mice with subtotal nephrectomy

Abstract Background and Aims The identification of novel roles for bone as a principal endocrine organ has grown in recent decades, being now recognized for its contribution to the regulation of numerous systemic functions. In previous studies, we observed that 5/6Nx mice with osteocytic deletion of phosphatase and tensin homolog (PTEN), exhibited higher bone volume in 5/6Nx mice, consistent with studies under normal renal conditions. However, we also noted a decrease in blood hemoglobin levels, prompting further exploration. This study aims to elucidate the causative actions by which specific PTEN deletion in osteocytes influences red blood cell (RBC) homeostasis and to identify its possible involvement in anemia development. Method To achieve this goal, we used mice with targeted PTEN deletion in osteocytes (PTEN Ocy-cKO) by crossing DMP1-Cre ± and PTENflox/flox mice, subjected to subtotal nephrectomy (5/6Nx) at 2 months of age. Two weeks post-surgery, bone and blood samples were collected for plasma biochemistry, blood count, RBC membrane integrity, and preliminary bone+bone marrow proteomic analysis. Cre-negative mice and animals with normal renal function were included as controls. Results Our findings revealed that PTEN Ocy-cKO mice, under both normal and reduced renal function conditions, showed higher bone volume than corresponding controls. In terms of blood homeostasis, PTEN Ocy-cKO mice with normal renal function showed splenomegaly and a lower number of circulating RBCs. Notably, PTEN Ocy-cKO mice undergoing 5/6Nx experienced a profound decrease in RBC number in only two weeks, independent of renal erythropoietin expression. Further exploration ruled out bone marrow failure as a cause, as the erythroid progenitor (CD45-CD71+Ter119+) population remained similar in both groups. Extramedullary hematopoiesis was observed in the spleen, in addition to increased circulating reticulocyte number in the PTEN Ocy-cKO mice. Finally, altered RBC membrane protein patterns in PTEN Ocy-cKO mice suggested reduced mechanical/osmotic resistance. Preliminary proteomic analysis identified downregulation of Slc4a1 (Band3) and Phosphofructokinase (Pfkm), whose deficiencies have been previously linked to anemia. Conclusion In conclusion, our results propose that osteocytes contribute to RBC homeostasis through a pathway downstream of PTEN, and open a new avenue for understanding anemia in chronic kidney disease and a potential target for future treatments.

#1912 Assessment of the dynamics of renal anemia in patients with atrial fibrillation and chronic kidney disease stage IIIb-V during anticoagulant therapy

Abstract Background and Aims Therapy with oral anticoagulants prevents the development of most ischemic strokes and systemic embolisms in patients with atrial fibrillation (AF) and chronic kidney disease (CKD), and also helps to increase life expectancy, improving its quality. It should be emphasized that with CKD, the risk of hemorrhagic complications also increases, which in turn can lead to the progression of renal anemia and deterioration in the patient's general condition. The main complication of anticoagulants is an increased risk of major bleeding, including intracranial, life-threatening bleeding. The purpose of the study is to assess the benefits and risks of anticoagulant therapy in patients with renal anemia in AF and stage IIIb-V CKD. Method From February 2022 to July 2023, 2983 patients with AF were admitted to cardiology departments. The majority of patients with AF had hypertension (94%), chronic heart failure (71%), coronary heart disease (65%), and type 2 diabetes mellitus (23%). CKD was diagnosed according to KDIGO criteria, glomerular filtration rate (GFR) was calculated using the CKD-EPI formula. Indications for anticoagulant therapy (ACT) were determined according to European guidelines for AF using the scales for assessing the risk of thromboembolic complications (TEC)—CHA2DS2-VASc and the risk of bleeding—HAS-BLED. Results GFR up to 45 ml/min/1.73 m2 was detected in 2189 (73%) patients with AF, GFR less than 45 ml/min/1.73 m2 in 794 (27%) patients with AF (CKD stages IIIb–V in 516 (65%) cases, for the first identified sustained decrease in glomerular filtration rate (FISD in GFR) of less than 45 ml/min/1.73 m2 was detected in 278 (35%) cases). Among patients with AF and CKD, renal anemia was diagnosed in 23% of cases, in 63% (n = 505) of cases with AF and GFR <45 ml/min/1.73 m2. With a GFR of 45-30 ml/min/1.73 m2, renal anemia was detected in 59%, with a GFR of 30-15 ml/min/1.73 m2—in 89%, with a GFR <15 ml/min/1.73 m2—in 97%, with FISD in GFR <45 ml/min/1.73 m2—in 51%. When stratifying thromboembolic risk according to the CHA2DS2-VASc scale in patients with AF and CKD stages IIIb–V, 0-1 points were scored by 1% (n = 11), 2-5 points by 53% (n = 420), ≥6 points by 46% (n = 363) patients. The results of the analysis of the risk of bleeding according to the HAS-BLED scale showed the following data: 0-1 point—8% (n = 64), 2 points—15% (n = 118), ≥3 points—77% (n = 612). When studying the frequency of ACT prescription, it was revealed that rivaroxaban was prescribed in 21%, apixaban—22%, dabigatran—10%, warfarin—25%, low molecular weight heparins—3%, ACT not recommended—9%, ACT of choice—10% of cases (Table 1). In mild renal anemia (in 39% of patients), taking ACT led to a reduction in the risk of developing TEC—RR 0.55 with 95% CI 0.38-0.79; in case of moderate renal anemia (in 47.3% of patients), the risk of TEC did not decrease RR 1.03 with 95% CI 0.69-1.58; with severe renal anemia (in 13.7% of patients), the risk of TEC was also not reduced—RR 1.6 with 95% CI 1.17-2.2). Conclusion Every fourth patient in the cardiology department with AF showed a decrease in GFR <45 ml/min/1.73 m2, while 1/3 of them had FISD in GFR <45 ml/min/1.73 m2, and it is in these patients that the most common the dose of the prescribed anticoagulant did not correspond to the GFR; 50% of patients with GFR <45 ml/min/1.73 m2 and 32% with GFR <30 ml/min/1.73 m2 are recommended to use direct oral anticoagulants. Patients with stage V CKD were not prescribed direct oral anticoagulants; in 50% of cases, none of the anticoagulants was recommended.

#2898 Exposure response model describing hematologic changes with chronic treatment of CKD anemia with vadadustat

Abstract Background and Aims Vadadustat (VADA) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate endogenous erythropoietin production, increasing iron mobilization and red blood cell production. VADA is approved in 36 countries globally and is indicated in the European Union for the treatment of symptomatic anaemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis and is an alternative to treatment with erythropoiesis-stimulating agents (ESAs). The aim of this work was to develop a predictive, semi-mechanistic model to understand the effects of VADA and erythropoiesis-stimulating agents (ESAs) on hemoglobin response and to evaluate the impact of intrinsic and extrinsic patient characteristics on that response for non-dialysis dependent (NDD) and dialysis-dependent (DD) patient populations. Method A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. Results A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. A similar model structure was found to describe early changes in RETICs and longer-term changes in Hb for both VADA and ESAs. In each case, the magnitude of response increases with increased drug exposure up to a maximum value (Emax), and the Emax values were similar between VADA and ESAs. Subject intrinsic predictors of response included eGFR, subject age, BMI, and serum albumin, while extrinsic factors affecting response included geographic region, limits on acceptable Hb values (which also differ by geographic region) and the presence of previous ESA treatment. Interestingly, Hb responses were also correlated with changes in serum hepcidin, a key regulator of iron homeostasis, following both VADA and ESA treatment. Differences between the response to VADA and ESA were also described, including differences in temporal changes in RETICs and Hb. Conclusion This model showed an exposure-response relationship between VADA or ESA treatment and changes in RETICs and Hb for ESA naïve or ESA-experienced CKD subjects. The model will be used to inform dosage recommendations for VADA based on patient characteristics.

#3026 Uncovering the potential of HIF-PH inhibitors to treat renal anemia

Abstract Background and Aims Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors (HIF-PHis) are a novel class of agents that were developed for the treatment of renal anemia. The agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production. This research aims to gauge the potential utilization and impact of HIF-PHis based on the perspectives of nephrologists who are based in the EU5. Method Data were collected via an independent online survey of 204 nephrologists based in the EU5 (UK, Germany, Italy, France, and Spain) in November 2023. Results EU5 nephrologists report that most dialysis and CKD non-dialysis patients with renal anemia who are on ESA therapy have an optimal response to treatment; however, a substantial proportion of patients experience a suboptimal response to treatment and up to 13% of patients across dialysis modalities are classified as ESA hypo-responders. Regardless of their geographic location, EU5 nephrologists position HIF-PHis to offer the most value in the CKD non-dialysis patient setting, with a perceived high level of opportunity (80%) for roxadustat to improve renal anemia outcomes among non-dialysis patients. Not surprisingly, the perceived advantages of an oral agent over an injectable medication for the treatment of renal anemia are more substantial for dialysis patients who are receiving home therapies (peritoneal and home hemodialysis) compared to those receiving in-center hemodialysis treatment. EU5 nephrologists also tend to believe that roxadustat represents a high level (64%) of opportunity to improve renal anemia outcomes in dialysis patients, with similar ratings observed for vadadustat (63%) in the same patient population. Specific to the use of HIF-PH inhibitors in the CKD non-dialysis setting, nephrologists are most concerned about patient compliance (51%), followed by safety compared to ESAs in general and as they relate to cardiovascular events (36%). When considering the use of HIF-PH inhibitors in the dialysis setting, nephrologists express similar concerns compared to the non-dialysis setting, with patient compliance (50%) ranked as the top concern, followed by safety compared to ESAs (38%), and the potential for off target effects (33%). Most EU5 nephrologists agree that HIF-PH inhibitors represent a more physiologic way of treating anemia of CKD compared to ESAs (70%) and many would like gain more clinical experience with the class of medications (63%). Current roxadustat treatment rates in dialysis are slowly increasing across the EU5 region, with slightly higher adoption in peritoneal dialysis patients (10%) compared to in-center hemodialysis patients (8%). Meanwhile, their self-reported uptake of roxadustat in CKD non-dialysis patients is also increasing over time, with the largest increase observed in CKD Stage 4 patients (9%). There is little consensus among EU5 nephrologists regarding their expected time to trial vadadustat once it is available, as nearly the same proportion of prescribers project that they will prescribe the agent to their dialysis patients within three months (36%), six months (23%), and within one year (28%). Conclusion With HIF-PHis having more of a physiologic mechanism of action, oral administration, and a similar safety profile compared to ESAs, broader adoption of the novel agents will potentially help address unmet needs and improve patient outcomes in the treatment of renal anemia for both CKD non-dialysis and dialysis patients.

Short versus long-acting erythropoiesis-stimulating agents for anemia management in Egyptian hemodialysis patients.

Chronic kidney disease (CKD) often results in renal anemia, impacting the well-being of patients and causing various negative consequences. Erythropoiesis-stimulating agents (ESAs) offer promising solutions for managing anemia in CKD. This study aimed to evaluate and compare the effectiveness, safety profile, and cost-effectiveness of short-acting (Eprex®) and long-acting (Aranesp®) ESAs. This comparative prospective cohort cost-effectiveness study was carried out over 6 months among adult Egyptian hemodialysis patients of either gender. Participants were categorized into two groups based on the type of ESA administered: the Eprex group, receiving epoetin alfa, and the Aranesp group, receiving darbepoetin alfa. These two treatment groups' efficacy, safety, and cost were analyzed and compared. Of 127 hemodialysis patients, 60 (47.2%) received Eprex, while 67 (52.8%) were treated with Aranesp. Target hemoglobin (Hb) was achieved by 50.6% of patients in the Eprex group versus 63.4% in the Aranesp group, with a significant difference (P < 0.001). Both treatment groups exhibited a similar safety profile, while Aranesp® was considered the cost-saving protocol. In hemodialysis Egyptian patients, Aranesp with extended dosing intervals proved to be more effective in achieving target Hb with comparable adverse effect profiles, a substantial cost-saving strategy, and offered time-saving advantages for medical staff workload compared to Eprex. The Clinicaltrial.gov registration ID is NCT05699109 (26/01/2023).

Erythropoietin hyporesponsiveness in non-alcoholic fatty liver disease.

Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness. To test our hypothesis, we evaluated the effect of EPO in healthy rats and rats with NAFLD induced by a high-fat, high-carbohydrate (HFHC) diet. After 12 weeks on the HFHC diet, NAFLD rats showed lower erythroid response to EPO treatment than healthy rats. We, then, determined that the primary cause of EPO hyporesponsiveness could be iron deficiency associated with inflammation, which reduces erythroid cell production. Specifically, the concentrations of hepcidin, ferritin, transferrin and white blood cells in NAFLD rats were 12.8-, 16.4-, 2.51- and 1.40-fold higher than those in healthy rats, respectively. However, erythroid cell types in the bone marrow of NAFLD rats were significantly reduced. In conclusion, our data suggest that NAFLD could be a risk factor for EPO responsiveness, which is attributed to functional iron deficiency associated with inflammation.

Clinical application and future perspectives of HIF-PH inhibitors

Anemia in chronic kidney disease (CKD) occurs due to insufficient production of erythropoietin to compensate for the decrease in hemoglobin. Anemia in CKD has traditionally been treated with periodic injections of erythropoiesis-stimulating agents (ESAs), which are recombinant human erythropoietin preparations. Although ESA improved anemia in CKD and dramatically improved the quality of life of patients, there are some patients who are hyporesponsive to ESA, and the use of large doses of ESA in these patients may have a negative impact on patient prognosis. Currently, HIF prolyl hydroxylase (HIF-PH) inhibitors have been approved in Japan as a new treatment for anemia in CKD. HIF-PH inhibitors activate HIF and promote the production of endogenous erythropoietin. The 2019 Nobel Prize in Physiology or Medicine was awarded for groundbreaking research that uncovered the HIF pathway. Because HIF-PH inhibitors improve both erythropoietin production and iron metabolism, they are expected to be effective in treating ESA hyporesponsiveness and solve the inconvenience of injectable preparations. On the other hand, its effects are systemic and multifaceted, and long-term effects must be closely monitored.

Anemia in Patients After Stem Cell Transplantation and in Kidney Transplant Recipients

Hematopoietic stem cell transplant (HSCT) is the treatment of choice in various hematologic diseases, and kidney transplantation (KTx) is the best therapy for end-stage kidney disease. Chronic kidney disease (CKD) occurs relatively often after both types of transplantations. Anemia after both HSCT and KTx may be due to CKD and other reasons. This study aimed to assess the prevalence of anemia to CKD in 156 prevalent patients after HSCT and 80 after KTx. According to the World Health Organization's definition (hemoglobin <13 g/dL for men and <12 g/dL for women), the prevalence of anemia in the studied cohort after HSCT was 13% in women and 35% in men and for those after KTx, it was29% in men and 11%. Anemia in KTx was found in 46% of patients, whereas CKD was present in 53%. After HSCT, anemia was associated with CKD in 56% of women and 17% of men. In KTx, anemia and CKD was diagnosed in 21% of patients. Patients with anemia after KTx had significantly lower glomerular filtration rate (GFR), hemoglobin, and significantly higher creatinine levels. Age was related to the estimated GFR (eGFR; r = -0.39, P < .001) in patients who underwent HSCT and had anemia. In patients without anemia, age was negatively related to eGFR (r = -0.56, P < .001) and the hemoglobin-to-platelet count (r = 0.62, P < .001). In KTx, hemoglobin was related to eGFR (r = 0.35, P < .001), and age was related to eGFR (r = -0.20, P < .05). The type of induction therapy immunosuppressive regimen (anti-thymocyte globulin vs basiliximab vs no induction) did not affect the prevalence of anemia in the KTx population studied. Anemia is relatively common in CKD after HSCT. In both CKD and coexistent anemia, nephrology referral is to be considered to optimize therapy, including nephroprotection.

Chemistry, Analysis, and Biological Aspects of Daprodustat, A New Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor: A Comprehensive Review.

The National Health and Nutrition Examination Survey (NHANES) carried out a survey between 2007-10 and found that as compared to the general population, the prevalence of anemia in chronic kidney disease (CKD) patients was twice high. Daprodustat is an investigational novel drug for the treatment of renal anemia. The objective of this study is to provide a comprehensive review of chemistry, synthesis, pharmacology, pharmacokinetic, and bioanalytical methods for the analysis of Daprodustat. To improve understanding, a review was carried out by creating a database of relevant prior research from electronic sources such as ScienceDirect and PubMed. The methodology is shown in the flowchart of the literature selection process. The drug was approved in 2020 for therapeutic purposes in Japan. It is a novel drug approved for the treatment of anemia in chronic kidney disease for oral administration. It is intended for adults who have undergone dialysis for a minimum of four months and are experiencing anemia as a result of chronic kidney disease. This review examines therapeutic, pharmacological, and analytical aspects related to the novel drug Daprodustat.

Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism.

Iron deficiency regulates the production of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) but also its cleavage, to generate both intact (iFGF23) and C-terminal (Cter)-FGF23 peptides. Novel studies demonstrate that independently of the phosphaturic effects of iFGF23, Cter-FGF23 peptides play an important role in the regulation of systemic iron homeostasis. This review describes the complex interplay between iron metabolism and FGF23 biology. C-terminal (Cter) FGF23 peptides antagonize inflammation-induced hypoferremia to maintain a pool of bioavailable iron in the circulation. A key mechanism proposed is the down-regulation of the iron-regulating hormone hepcidin by Cter-FGF23. In this manuscript, we discuss how FGF23 is produced and cleaved in response to iron deficiency, and the principal functions of cleaved C-terminal FGF23 peptides. We also review possible implications anemia of chronic kidney disease (CKD).

Strategies for Managing Anemia in Chronic Kidney Disease

Anemia is a common complication in chronic kidney disease (CKD) and is associated with decreased quality of life, deteriorating kidney function, increased illness, higher mortality rates, and elevated healthcare costs. Management of CKD-related anemia aims to enhance renal function (when feasible) and bolster red blood cell production. Anemia in chronic kidney disease (CKD) stems from a variety of factors, including reduced erythropoietin (EPO) production, inadequate iron availability or functionality, and inflammation leading to heightened levels of hepcidin, among other causes. Typical treatment for CKD-related anemia involves administering oral or intravenous iron supplements in conjunction with erythropoiesis-stimulating agents (ESAs). Over the past decade, erythropoiesis-stimulating agents (ESAs) have proven effective in boosting hemoglobin (Hb) levels for many patients. However, concerns about their safety, particularly regarding increased cardiovascular risk—especially at high doses and in hyporesponsive patients—have emerged. As a result, there's been a shift towards adopting more cautious Hb targets. Iron deficiency is widespread among CKD patients, particularly in those not undergoing dialysis. While iron supplementation has traditionally been used to support anemia management, there's growing recognition of the potential benefits of intravenous iron therapy, especially in the context of heart failure. HIF prolyl hydroxylase inhibitors are promising new drugs being clinically evaluated as alternatives to ESAs for anemia treatment in CKD patients. Initial data suggest they effectively boost endogenous erythropoietin production with potential benefits like lower peak concentrations, efficacy in inflamed patients, and improved iron utilization. However, further research is needed to confirm their safety and efficacy in the long term use.&#x0D; Keywords: anemia, chronic kidney disease, erythropoiesis-stimulating agents, iron, HIF-prolyl-hydroxylase inhibitors

Daprodustat: A Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia of Chronic Kidney Disease.

The objective was to review the safety and efficacy of daprodustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) in the treatment of anemia of chronic kidney disease (CKD). A literature search was conducted in MEDLINE, EMBASE, and ClinicalTrials.gov using the keywords "daprodustat," "GSK1278863," and "hypoxia-inducible factor-prolyl hydroxylase inhibitors" from January 2010 through November 2023. Literature was included if it evaluated pharmacology, pharmacokinetics, efficacy, and/or safety of daprodustat in human subjects and was reported in English. The manufacturer's product monograph was also utilized. Daprodustat significantly increased hemoglobin levels in CKD patients on dialysis (difference 0.18 g/dL) and not on dialysis (difference 0.08 g/dL) over 52-week treatment periods compared with erythropoiesis stimulating agents (ESA) in Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat (ASCEND)-D and ASCEND-ND, respectively. First occurrence of major adverse cardiovascular events (MACEs) was similar between daprodustat and ESAs in both trials. Daprodustat can be used in patients with CKD on dialysis and already receiving an ESA for at least 6 weeks to further increase serum hemoglobin levels without increasing the risk of MACE. Adverse effects of daprodustat that may occur more than ESAs include headache, emesis, and thrombosis. Daprodustat is a novel oral, non-iron therapy for treatment of anemia of CKD. It was Food and Drug Administration approved in 2023 in patients already receiving dialysis for at least 4 months but not in non-dialysis patients. Long-term data for safety and additional benefits are pending.